Department of Pharmaceutical Biochemistry

Department

Professor Yukihiko Sugimoto
Lecturer Soken Tsuchiya
Assistant Professor Tomoaki Inazumi

Research themes

[Names and Summaries of Research Projects]

1. Identification of lipid mediator flow linked to diseases and its molecular mechanism by focusing on prostaglandin receptors. (Y. Sugimoto)

2. Identification and clinical manipulation of tissue-specific functions of mast cells linked to diseases. (Y. Sugimoto & S. Tsuchiya)

3. Molecular mechanisms underlying regulation of esophageal cancer by micro RNA.(S. Tsuchiya)

1) Aspirin-like drugs elicit their therapeutic effects through suppression of biosynthesis of prostaglandins (PGs), which exert a wide variety of actions by acting on the PG receptors on the neighboring cells (Fig. 1). The final output of PG actions has been shown to depend on both intracellular and extracellular circumstances, and their exact molecular mechanisms remain elusive. To clarify these points, we examine the effect of PG receptor deficiency on several processes and therein molecular events in the nervous, immune and reproductive systems. Taking advantages of gene-manipulated mice for a full set of PG receptors, in combination with lipidolomics, single cell technology and structural biology, this study aims to identify novel lipid-metabolic pathways that are lined to diseases, and thereby to provide rationales for novel therapuetic strategies to control the diseases by targeting the specific lipid pathways.

2) Mast cells (MCs) are derived from hematopoietic stem cells and play important roles in allergic responses, innate immunity and defense against parasite infection. Unlike other blood cells, MCs migrate into peripheral tissues as immature progenitors and differentiate into mature mast cells. One of the unique features of MCs is that they show a variety of phenotypes depending on the different tissue microenvironment of their maturation. In MCs, various MC-specific serine proteases are stored in the secretory granules, and their gene and protein expressions are dramatically altered when their cell environment is altered. In addition, recent studies have shown that mature MCs vary in terms of what surface receptors and lipid mediators they express. Because each mast cell population in vivo must play a specific role in the body, it is important to determine the character of each population of MCs. To overcome these problems, we established a method of RNA amplification from intact MCs isolated from frozen tissue sections, which enables us to conveniently obtain the global gene expression pattern of MCs in various tissues.

3) MicroRNAs are evolutionarily conserved small noncoding RNAs (20-23 nucleotides) that bind to complementary sequences in the 3' UTR of target mRNAs and regulate gene expression by the cleavage of target mRNAs and/or translational inhibition. Recently, we identified miR-210 as one of the microRNAs that is markedly differentially expressed between epithelial cells and epithelia cancer cells, although the roles of miR-210 during differentiation into cancer remained unknown. Moreover, we found that miR-210 inhibits cancer cell survival and proliferation. We are now investigating molecular mechanisms underlying suppression of esophageal squamous cell carcinoma proliferation by miR-210.

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Fig.1. Five prostaglandins synthesized by cyclooxygenase pathway exert a wide variety of actions via eight types and subtypes of receptors expressed on neighboring cells.

Key Words

Prostaglandins, Prostaglandin receptors, Eicosanoids, Aspirin, Non-steroidal anti-inflammatory drugs, Lipid mediators, Metabolome, Single cell-based analysis, Knock-out mice, GPCR, Structure-function relationship, Acute inflammation, Allergy, Auto-immune diseases, Chronic inflammation, Mast cells, Inate immunity, Acquired immunity, Female reproduction, Metabolic diseases, Contact dermatitis, Esophageal cancer, Micro-RNA, Transcriptome, Zebrafish, Development, Hematopoietic stem cells, Angiogenesis.